The last decade brought a revolution in rheumatoid arthritis (RA) therapies and an immediate need for reliable measurement of disease progression and response. Despite the strides in diagnostic imaging capabilities, conventional approaches in MRI, ultrasound, radiography, and CT face a variety of limitations that do not permit widespread application to RA assessment - e.g., limited spatial and contrast resolution, quantitation, reproducibility, and cost / accessibility. An emerging advance in CT promises to transcend the conventional limitations of this modality in rheumatology - high-resolution cone-beam CT (CBCT) with dual-energy (DE) material decomposition. We have recently developed a novel platform for CBCT dedicated to extremity imaging, demonstrating spatial and contrast resolution beyond the limits of conventional CT at reduced dose. Specifically, the system provides isotropic, sub-millimeter spatial resolution and soft-tissue contrast including synovial tissues, cartilage, tendons, and ligaments through DE decomposition. The resulting technology could provide a powerful addition to the rheumatologist's arsenal through access to high-quality imaging with cost, workflow, and site considerations appropriate to rheumatology clinical settings. We hypothesize that high- quality DE-CBCT combined with advanced, fully 3D image analysis will provide reliable visualization and quantitative metrics of RA. We will address this hypothesis through the following Specific Aims: 1.) Optimization of DE-CBCT image quality in rheumatological imaging tasks, including non-contrast exams (endogenous soft-tissues) and contrast-enhanced exams (exogenous Gd or iodine); 2.) Development of quantitative image-based metrics that leverage the superior spatial and contrast resolution of DE-CBCT for measurement of early-intermediate RA findings following the current gold standard in image-based assessment [the RA MRI score (RAMRIS)] - namely, synovial membrane volume (SMv), bone marrow edema volume (BMEv), and erosion volume (Ev) - as well as novel metrics of fully 3D intra-articular and subchondral morphology that have been identified as potential new correlates of rheumatic disease; and 3.) Translation to a pilot study in 20 RA patients on the prototype scanner to evaluate the reproducibility of DE-CBCT and associated image-based metrics (test-retest within a 1-week interval analyzed in paired t-tests) and the validity of DE-CBCT metrics relative to RAMRIS (sensitivity / specificity in scoring of RA pathology). An interdisciplinary team combining expertise in engineering, radiology, rheumatology, and biostatistics is assembled to accomplish these goals. Successful completion of the research will identify optimal imaging techniques for DE-CBCT of RA, develop quantitative image-based metrics of early, intermediate, and late RA disease (with applicability to MRI and DE-CT), and provide essential quantitation of reproducibility and validity of DE-CBCT in RA assessment as a first step toward applying DE-CBCT for quantitative measurement of RA progression and therapy response.